A mouse model of gestational glucose intolerance through exposure to a low protein diet during fetal and neonatal development.

Gestational diabetes mellitus (GDM) is an increasingly prevalent form of diabetes that appears during pregnancy. Pathological studies link a failure to adaptively increase maternal pancreatic β-cell mass (BCM) in pregnancy to GDM. Due to the scarcity of pancreatic samples from GDM patients, we sought to develop a novel mouse model for impaired gestational glucose tolerance. Mature female C57Bl/6 mouse offspring (F1) born to dams fed either a control (C) or low-protein (LP) diet during gestation and lactation were randomly allocated into two subsequent study groups: pregnant (CP, LPP) or non-pregnant (CNP, LPNP). Glucose tolerance tests were performed at gestational day (GD) 9, 12 and 18. Subsequently, pancreata were removed for fluorescence immunohistochemistry to assess α-cell mass (ACM), BCM and β-cell proliferation. An additional group of animals was used to measure insulin secretion from isolated islets at GD18. LPP females displayed glucose intolerance compared to CP females at GD18 (P < 0.001). BCM increased threefold at GD18 in CP females. However, LPP females had reduced BCM expansion (P < 0.01) concurrent with reduced β-cell proliferation at GD12 (P < 0.05). LPP females also had reduced ACM expansion at GD18 (P < 0.01). LPP islets had impaired glucose-stimulated insulin secretion in vitro compared to CP islets (P < 0.01). Therefore, impaired glucose tolerance during pregnancy is associated with a failure to adequately adapt BCM, as a result of reduced β-cell proliferation, in addition to lower glucose-stimulated insulin secretion. This model could be used to evaluate novel interventions during pregnancy to increase BCM or function as a strategy to prevent/reverse GDM.